This invention relates to a novel process for producing phosphatidylcholine derivatives useful as elementary material of liposomes, etc. used in the field of drug-delivery system (DDS) and clinical diagnostic drug.
As the method for producing diacyl-phosphatidylcholines (hereinafter simply referred to as "DAPC"), acylation of glycero-phosphatidylcholine is usually adopted and has been widely practised hitherto. This method can roughly be classified into the following four processes.
(1) Acylation using fatty acid chloride (Can. J. Biochem. Physiol., 37, 953 (1959), etc.);
(2) Acylation using 1-acylimidazole (U.S. Pat. No. 4,130,571);
(3) Acylation using fatty acid anhydride in the absence of solvent (Biochim. Biophys. Acta, 187, 520 (1969), etc.);
(4) Acylation using fatty acid anhydride in the presence of an esterification catalyst such as N,N-dimethyl-4-aminopyridine, N,N-pyrrolidinopyridine or the like (U.S. Pat. No. 4,690,784).
However, all these processes are disadvantageous in the following points. Thus, the acylation process (1) using fatty acid chloride is disadvantageous in that the reaction cannot progress sufficiently unless a basic catalyst such as pyridine and the like is used, and when such a basic catalyst is used the catalyst remaining in the system after the reaction must be removed by the use of ion exchange resin or the like, which makes the procedure troublesome. The acylation process (2) which comprises converting a fatty acid into imidazole derivative to activate the acyl group and then carrying out acylation with the derivative is disadvantageous in that the reaction takes a long period of time and gives only a low yield, the acylating agent liberates imidazole of which separation and removal is troublesome similarly to above, and the acylating agent is expensive. The acylation process (3) which comprises carrying out acylation in the absence of solvent by the use of a fatty acid anhydride is disadvantageous in that the reaction system has a high viscosity, workability of the process is not good, and the reaction takes a long period of time, so that the process is by no means adoptable commercially. The acylation process (4) which comprises carrying out acylation by the use of fatty acid anhydride in the presence of a basic catalyst is disadvantageous in that the basic catalyst remaining after the reaction must be removed with ion exchange resin or the like, which results in increasing the number of steps and makes the procedure troublesome.